Cinobufagin Enhances the Sensitivity of Cisplatin-Resistant Lung Cancer Cells to Chemotherapy by Inhibiting the PI3K/AKT and MAPK/ERK Pathways

Lung cancer patients always develop serious chemotherapy resistance after long-term use of cisplatin treatment. It has been demonstrated that the combination of cisplatin (DDP) with other chemotherapy drugs may significantly reduce drug resistance. Cinobufagin (CB) showed potent anti-tumour effect against lung cancer. However, the relevance of CB and DDP resistance in lung cancer remains unclear. This article will study the effects of CB on reversing lung cell resistance. The apoptosis was rescued by flow cytometry analysis and TUNEL staining. The invasiveness was rescued by invasion assay. The mRNA and apoptosis-related proteins were estimated by qRT-PCR analysis and Western blot analysis, respectively. In vivo antitumor activities were investigated by subcutaneous xenograft assay. The present study firstly demonstrated that the sensitivity of DDP in DDP-resistant A549 (A549/DDP) cells was enhanced when treated with CB. Moreover, CB combined with DDP weakened the proliferation and increased apoptosis of A549/DDP cells. In addition, the expression level of Bcl-2 was increased, whereas Bax and caspase-3 were activated when A549/DDP cells were treated with both drugs. After treatment with IGF1 or PMA and mixed drugs (CB + DDP), the expressions of P-AKT, P-PI3K, P-MEK1/2 and P-ERK1/2 were increased. Finally, the results of in vivo experiments showed that the combination of DDP and CB significantly reduced the growth of tumours derived from A549/DDP cells. The combination of CB and DDP can be considered an effective strategy to increase the sensitivity of DDP-resistant lung cancer cells to DDP by inhibiting the PI3K/AKT and MAPK/ERK pathways.